Edoxaban tosylate monohydrate, an oral anti-coagulant, is marketed in the United States as SAVAYSA®, and is indicated to reduce the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF), and for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) following 5 to 10 days of initial therapy with a parenteral anticoagulant. Edoxaban (1) is a factor Xa (“FXa”) inhibitor having the chemical name N1-(5-chloro-2-pyridinyl)-N2-[(1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-[[(4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridin-2-yl)carbonyl]amino]cyclohexyl]ethanediamide, and the following structural formula:

U.S. Pat. No. 7,365,205 B2 discloses preparation of Edoxaban (1) and salts thereof as a member of a class of diamine derivatives that inhibit FXa. Two routes for the preparation of Edoxaban, as shown in Schemes 1 and 2 below, are provided. However, the synthesis of intermediate (III) in either route requires the use of sodium azide as a nitrogen source for the introduction of the two cis-amino groups on the cyclohexyl ring. Sodium azide is a highly toxic reagent having deleterious effects on the environment, which poses safety concerns when used on an industrial scale. Additionally, following mesylation of intermediate (II), the azide displacement of the mesyloxy group to yield intermediate (III) produces as much as 10% to 15% of the undesired trans-isomer (III-B), which can carry through subsequent steps as an impurity if not removed. A discussion of the formation of this impurity is provided in Nagata et al. Bioorg. Med. Chem. Lett. 2008, 18(16), 4587-4592.


Additional processes for preparation of Edoxaban are described in U.S. Pat. No. 8,686,189 B2, which follows a similar approach to that employed in U.S. Pat. No. 7,365,205 B2 (depicted in Scheme 2) for preparation of free base (X). Although the use of an azidation reagent in this process has been reduced to one step, an azidation process is still required. Additionally, the required azidation step is lengthy, generally taking in excess of 70 hours to complete, which leads to a corresponding increase in product cycle times if the process is used commercially. The above-noted deficiencies related to the generation of the undesired trans-isomer (IIIB) persist in this approach, and are reportedly controlled by isolation of the cis-isomer of compound (X) as an oxalate salt (X-A), with a concomitant loss of yield that is associated with the purge of the trans-isomer.

U.S. Pat. No. 8,357,808 B2 discloses conditions for the preparation of Edoxaban intermediate (XI) (see Scheme 2). In this process, the generation of ‘Impurity X’, which is formed during the subsequent reaction of oxalate salt (X-A), is reportedly minimized by controlling the order of addition of reaction components, and adding a tertiary amine in divided portions. However, this approach to impurity control can be operationally challenging to implement on an industrial scale.

Further processes for the preparation of Edoxaban and/or intermediates thereof are disclosed in US 2012/0035369 A1, CA 2 940 001 A1, CN 104761571 A and CN 105198776 A. However, where these processes reference the use of the core cis-diamino cyclohexyl unit, it is prepared using azidation, which has the drawbacks noted above.
In US 2016/0016974 A1, a process is disclosed for preparation of Edoxaban and intermediates thereof where the cis-diamino groups on the cyclohexyl ring in compounds (XVIII) and (XIX) are introduced by an intramolecular cyclization substitution reaction as part of a multi-step process, as shown in Scheme 3.

In US 2016/0016974 A1, the treatment of intermediate (XVII) with base provides thiadiazole (XVIII), reportedly by progression through an aziridine intermediate and migration of the carbamate-protected nitrogen, which is said to control the stereo- and regio-chemistry of the two amino positions. The free amine position of compound (XIX) is further reacted with a chloropyridinyl amino(oxo)acetate moiety, followed by deprotection of the carbamate group and coupling with the tetrahydrothiazolo pyridine unit to yield Edoxaban. The cyclization/substitution steps provided in this route directs the carbamate protecting group RxCO2— to the position shown in compound (XIX) in Scheme 3. However, careful control of the subsequent coupling conditions using this intermediate is required to avoid generation of ‘Impurity X’.
In view of the foregoing issues associated with the known process for the preparation of Edoxaban, there remains a need in the art for improved processes for use in the preparation of Edoxaban that reduce the number of steps involved, provide greater control of impurities, and reduce the need to use undesirable reagents.